OA11144A - Compounds and method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids - Google Patents

Abstract

This invention relates to a method of preparing a compound of formula (I) by treating a compound of formula (II) with lithium bromide, magnesium bromide and the like.

Description

1 1 011144

Compounds and Method for Preparing Substituted 4-Phenyl-4-cyanocyclohexanoic Acids

Scope of the Invention

This invention covers intermediates and a synthetic route for making 4- 5 cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanoic acid and its analogs.This acid and its named analogs are sélective for inhibiting the catalytic site in thephosphodiesterase isoenzyme denominated IV (PDEIV hereafter) and as such theacids are useful in treating a number of diseases which can be moderated byaffecting the PDE IV enzyme and its subtypes. 10 Area of the Invention

Bronchial asthma is a complex, multifactorial disease characterized byréversible narrowing of the airway and hyper-reactivity of the respiratory tract toextemal stimuli.

Identification of novel therapeutic agents for asthma is made difficult by the15 fact that multiple mediators are responsible for the development of the disease.

Thus, it seems unlikely that eliminating the effects of a single mediator will hâve asubstantial effect on ail three components of chronic asthma. An alternative to the"mediator approach" is to regulate the activity of the cells responsible for thepathophysiology of the disease. 20 One such way is by elevating levels of cAMP (adenosine cyclic 3’,5 - monophosphate). Cyclic AMP has been shown to be a second messenger mediatingthe biologie responses to a wide range of hormones, neurotransmitters and drugs;[Krebs Endocrinology Proceedings of the 4th International Congress ExcerptaMedica, 17-29,1973]. When the appropriate agonist binds to spécifie cell surface 25 receptors, adenylate cyclase is activated, which converts Mg+^-ATP to cAMP at anaccelerated rate.

Cyclic AMP modulâtes the activity of most, if not ail, of the cells that 'contribute to the pathophysiology of extrinsic (allergie) asthma. As such, anélévation of cAMP would produce bénéficiai effects including: 1) airway smooth 30 muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression ofneutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibitionof monocyte and macrophage activation. Hence, compounds that activate adenylatecyclase or inhibit phosphodiesterase should be effective in suppressing theinappropriate activation of airway smooth muscle and a wide variety of 2 011144 inflammatory cells. The principal cellular mechanism for the inactivation of cAMPis hydrolysis of the 3’-phosphodiester bond by one or more of a family of isozymesreferred to as cyclic nucléotide phosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucléotide phosphodiesterase(PDE) isozyme, PDEIV, is responsible for cAMP breakdown in airway smoothmuscle and inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: PotentialTargets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Bames, ed. IBC Technical Services Ltd., 1989]. Research indicates that inhibition of thisenzyme not only produces airway smooth muscle relaxation, but also suppressesdegranulation of mast cells, basophils and neutrophils along with inhibiting theactivation of monocytes and neutrophils. Moreover, the bénéficiai effects of PDEIV inhibitors are markedly potentiated when adenylate cyclase activity of target cellsis elevated by appropriate hormones or autocoids, as would be the case in vivo. ThusPDE TV inhibitors would be effective in the asthmatic lung, where levels ofprostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated.

Such compounds would offer a unique approach toward the pharmacotherapy ofbronchial asthma and possess significant therapeutic advantages over agentscurrently on the market.

The process and intermediates of this invention provide a means for makingcertain 4-substituted-4-(3,4-disubstitutedphenyl)cyclohexanoic acids which areuseful for treating asthma, and other diseases which can be moderated by affectingthe PDE IV enzyme and its subtypes. The final products of particular interest arefully described in U.S. patent 5,552,483 issues 03 September 1996. The informationand représentations disclosed therein, in so far are that information and thosereprésentations are necessary to the understanding of this invention and in itspractice, in total, are incorporated herein by reference.

Summary of the Invention

This invention relates a method for making a compound of formula I

R R" R. ‘3 (I)

Rl is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties may beoptionally substituted with one or more halogens; m is 0 to 2; 3 011144 n is 1 to 4;r is 0 to 6; R4 and R5 are independently selected from hydrogen or a Ci_2 alkyl; Rô is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-H polycycloalkyl,tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl,tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containingone or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties maybe optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when Rô is hydroxyl, then m is 2; or b) when Rô is hydroxyl, then r is 2 to 6; or c) when Rô is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when Rô is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then Rô is other than H in-(CR4R5)nO(CR4R5)mRô; X is YR2, halogen, nitro, NH2, or formyl amine; X2 is O or NR8; Y is O or S(O)m^,m’is 0,1, or 2; R2 is independently selected from -CH3 or -CH2CH3 optionally substitutedby 1 or more halogens; R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, -CH=CR8’R8\ cyclopropyl optionally substituted by R8\CN, ORs, CH2OR8, NRsRlO, CH2NR8RIO, C^H, C(O)ORs, C(0)NR8RlO, orC=CR8’;

Rg is hydrogen or C 1.4 alkyl optionally substituted by one to three fluorines;

Rg’ is Rs or fluorine;

RlOis ORs or Ru;

Rl 1 is hydrogen, or C 1,4 alkyl optionally substituted by one to threefluorines; Z’ is O, NR9, NOR8, NCN, C(-CN)2, CRgCN, CR8NO2, CR8C(O)OR8,CRsC(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NR8R8; R’ and R" are independently hydrogen or -C(O)OH; which method comprises treating a compound of formula II(a) or ïï(b) 4 011144

where R,, R3, X2 and X are the same as for formula (I), with lithiumbromide or magnésium bromide in a polar solvent at a température between about60° and 100° C, optionally under an inert atmosphère for a time sufficient for thereaction to go to completion.

This invention also relates to compounds of formula Π per se.

In another aspect this invention relates to a one-pot method for making theketone of formula ΙΠ starting with isovanillin,

where Rj, R3, X2 and X are the same as for formula (I), as more fullydescribed herein below.

In yet a third aspect this invention relates to a process for preparing acompound of formula I which process comprises treating a compound of formula(IV) using an alkali métal cyanide, for example LiCN, in a compatible solvent suchas dimethylformamide which contains a small proportion of water

where, in formula III, R], X and X2 are the same as in formula I.

In a further embodiment this invention relates to a process for making a . compound of formula I comprising treating an acyl nitrile of formula V with water.

C(O)CN (V)

The X, X2 and Rj groups in formula V are the same as those in formula I. 5 011144

In yet a further embodiment this invention relates to compounds offormula Π

Ri is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR6, θΓ -(CR4R5)rR6 wherein the alkyl moieties may beoptionally substituted with one or more halogens; m is 0 to 2;n is 1 to 4;r is 0 to 6; R4 and R5 are independently selected from hydrogen or a Ci-2 alkyl; R(5 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7.11 polycycloalkyl,tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl,tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containingone or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties maybe optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when Rô is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when Rô is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then Rô is other than H in-(CR4R5)nO(CR4R5)mR6; X is YR2, halogen, nitro, NH,, or formyl amine; X2 is O or NR8; Y is O or S(O)m’;m’isO, l,or2; R2 is independently selected from -CH3 or -CH2CH3 optionally substitutedby 1 or more halogens; R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, -CH=CR8’R8’. cyclopropyl optionally substituted by R8’, 6 011144 CN, ORs, CH2OR8, NRsRlO, CH2NR8Rl0» C(Z’)H, C(O)ORg, C(O)NRsRl0, or

CbCR8’ R8 is hydrogen or C 1.4 alkyl optionally substituted by one to three fluorines;

Rg’ is R8 or fluorine;

RiOisORsorRii;

Rl 1 is hydrogen, or C 1.4 alkyl optionally substituted by one to threefluorines; Z’ is O, NR9, NORg, NCN, C(-CN)2, CR8CN, CR8NO2, CRsC(O)OR8,CRgC(O)NRgRg, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NRgR8, and T is CN or SO2R where R is Ci.galkyl or Co_3alkylphenyl.

Spécifie Embodiments of the Invention

This process involves a nine step synthesis for preparing certain 4-substituted-4-(3,4-disubstitutedphenyl)cyclohexanoic acids. The starting material isisovanillin, 3-hydroxy-4-methoxybenzaldehyde, or an analog thereof. "Analog"means another 3 and/or 4 position substituent conforming to the définitions of R,, R3,X2 and X in the définition of formula (I).

The compounds which are made by this process are PDEIV inhibitors. Theyare useful for treating a number of diseases as described in U.S. patent 5,552,438issued 3 September 1996.

The preferred compounds which can be made by this process are as follows:

Preferred Ri substitutents for the compounds of ail named formulas areCH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl unsubstituted orsubstituted with OHC7-11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl,tetrahydrofuran-3-yl, benzyl or Cl-2 alkyl unsubstituted or substituted by 1 or morefluorines, -(CH2)l-3C(O)O(CH2)0-2CH3, -(CH2)l-3O(CH2)0-2CH3, and-(CH2)2-4OH.

Preferred X groups for Formula (I), (Π) or (ΙΠ) are those wherein X is YR2and Y is oxygen. The preferred X2 group for Formula (I) is that wherein X2 is -oxygen. Preferred R2 groups are a Ci-2 alkyl unsubstituted or substituted by 1 ormore halogens. The halogen atoms are preferably fluorine and chlorine, morepreferably fluorine. More preferred R2 groups are those wherein R2 is methyl, orthe fluoro-substituted alkyls, specifically a Ci-2 alkyl, such as a -CF3, -CHF2, or-CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.

Most preferred are those compounds wherein Ri is -CH2-cyclopropyl,cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 isoxygen; and R2 is CF2H or methyl; and R3 is CN. 7 011144 A représentative schematic of this process is set out in Scheme I. Thisgraphical représentation uses spécifie examples to illustrate the general methodologyused in this invention. 7 8 011144

Scheme I

9 011144

Referring to Scheme I, isovanillin, 3-hydroxy-4-methoxybenzaldehyde, is areadily available starting material. It can be alkylated with an RjX moiety (X = Cl, 10 Br, and I) as represented by cyclopentyl chloride. The reaction vessel is first flushedwith an inert gas, for example nitrogen. A polar solvent such as DMF is then added 10 011144 to the vessel, then the isovanillin, then the RjX adduct, and some base. About 2équivalents of the R,X adduct versus the isovanillin are used. Likewise about 2équivalents of base are used, again relative to the isovanillin. The base can be anyinorganic base or a carbonate. Here it is illustrated by potassium carbonate. Thevessel contents are heated to about 125° C for about 90 to 120 minutes in which timethe reaction will hâve gone to completion. The vessel contents are cooled toambient température, fîltered to remove the inorganic salts, and washed with analcohol such as methanol. This filtrate contains the aldéhyde, labeled 1-1.

The aldéhyde is then reduced to the alcohol using an inorganic reducingagent. To do this the filtrate from the foregoing reaction is treated with sodiumborohydride and after workup affords the desired alcohol, 1-2 in 97% overall yieldfrom isovanillin. This is achieved by cooling the filtrate to about 0° C after which areducing agent, here sodium borohydride, is added. About 0.25 to 0.5 équivalents ofthis reducing agent is used. The température is keep at about 0° C during the additionof the reducing agent and for about 30 to 40 minutes thereafter. Then thetempérature is allowed to rise to about room température after which about one-halfan équivalent of HCl is added to the reaction vessel. The alcohol is then extractedinto an organic solvent, toluene is illustrated, and washed with dilute sodiumbicarbonate.

The top organic layer containing the alcohol is then treated with excessconcentrated hydrochloric acid at ambient température to afford, after workup, thedesired benzyl chloride 1-3. The chloride is isolated as a w/w solution in an amidesolvent, DMF is illustrated, and treated with about a 50% molar excess of sodiumcyanide at a mildly elevated température, here illustrated as 55° C. This affords thedesired nitrilel-4. The nitrile is isolated as a w/w solution in an appropriate solventsuch as anhydrous acetonitrile and used directly in the next step.

The nitrile solution is charged with methyl acrylate. It is cooled to about -10° C, and slowly treated with a catalytic amount of Triton-B in the same solvent asused to dissolve the nitrile. The methyl acrylate is added in a 3 to 4-fold excess.

The reaction is complété within 30 to 45 minutes after which the acrylate addition,the pimelate product, 1-5, is isolated as a w/w solution in toluene and treated withabout 2 équivalents of sodium methoxide at about 75° C to give the β-keto-ester 11 011144 product, 1-6. The reaction solution is cooled and neutralized to pH 7 with mineraiacid such as 6N hydrochloric acid. The solution is charged with dimethyl sulfoxide,sodium chloride, water, and heated, for example to about 150° C, to effect thedécarboxylation to give 1-7. The ketone, 1-7, is isolated from the solvent System asan off-white solid.

The dicarbonitrile 1-8 is prepared from the ketone by treating the ketone withchloroacetonitrile in the presence of an inorganic base and a catalytic amount ofbenzyltriéthylammonium chloride (BTEAC). The ketone is charged into a mixtureof strong base (aqueous potassium hydroxide) and a water miscible solvent such astetrahydrofuran. A slight excess of chloroacetonitrile is added at reducedtempérature, about 0° C or thereabouts. The reaction is maintained at about thattempérature for the duration of the reaction, usually about 1 hour. The product isisolated and usually it is crystalline.

The dicarbonitrile is converted to the cyclohexanecarboxylic acid using aLewis acid catalyst; water is also needed to drive the reaction to the acid. Withoutwater intermediates l-10a and 1- 10b may dimerize. This reaction is carried out bycharging a vessel with solvents, in this instance exemplified by DMF, acetonitrileand water, and the Lewis acid (about 1.5 équivalents), LiBr is illustrated, sweepingthe vessel with an inert gas, adding the dicarbonitrile Ha or nb, or a mixture of Haand Ilb and heating the vessel and its contents to about 100° C for a number ofhours, 8 hours being an example. The acid is isolated by conventional means.

It should be noted that this reaction, that is the conversion of the epoxide tothe acid, involves several intermediates which do not need to be isolated. It has beenfound that treating the epoxide with LiBr yields intermediates l-9a and l-9b.Intermediate l-9a is formed when LiBr is added to the reaction pot. Butintermediate l-9a converts back to the epoxide under the recited reaction conditions.Intermediate l-9b is also formed but apparently reacts rapidly to form intermediatessuch as enolate A, l-10a and 1 -10b etc leading to product. So it appears l-9a and 1-9b are formed, but that l-9a converts back to the epoxide which ultimately forms 1-9b which is then converted to other intermediates enroute to forming the acids of 1-1 la and 1-1 lb. Parenthetically the désignation "0M(H)" in l-9a and 1 -9b means themétal sait of the alcohol or the alcohol per se, depending on the reaction conditions. 12 011144

Intermediate l-9b is believed to convert to the acyl nitriles of formulas l-10a and 1-10b via the proposed bracketed intermediate. The existence of the proposedbracketed intermediate (enolate) has not been fully confirmed. And while the acylnitriles of l-10a and 1- 10b hâve not been directly observed, indirect evidence existsfor these compounds by virtue of the fact the bis-condensation product dimer B wasisolated and is analogous to reported compounds where a similar bis-condensate isthe product of an acyl nitrile.

Scheme 2

C(O)CN CN-

Ar "CN l-10a/b

Dimers such as dimer A are known to form from the likes of acyl nitriles 1-lOa/b in the presence of HCN (Thesing, J.; Witzel, D.; Brehm, A. Angew Chem..1956,68,425; and Hunig, S.; Schaller, R. Angew. Chem. Int. Ed. Engl.. 1982,21,36).

And in addition, authentic samples of intermediates l-10a and l-10b wereprepared and found to convert to acids 1-1 la and 1-1 lb when exposed to water. Theequitorial isomer l-10a converted to the acid in an equitorial/axial ratio of about98:2 while the axial isomer l-10a isomerized to a perponderance of the equitorialisomer 1-1 la (77:23). It is believed the axial acyl nitrile couverts to the equitorialacyl nitrile via the proposed bracketed enolate intermediate.

The second, following reaction scheme illustrâtes preparing the acids offormula (I) from the bromoaldehyde of formula (IV).

Scheme 3 13 011144

The following examples are provided to illustrate spécifies of the invention,not to limit it. What is reserved to the inventors is set forth in the daims appendedhereto.

Spécifie Examples

Example 1

Préparation of 3-cyclopentyloxy-4-methoxybenzaldehyde. A 12 liter round bottom flask equipped with an overhead stirrer, internaithermometer, and a reflux condensor equipped with a nitrogen inlet was flushed withnitrogen. The flask was charged with. dimethylformamide (2.4 L), isovanillin (350 g,2.3 mol, 1 équivalent), cyclopentyl chloride (481 g, 4.6 mol, 2.0 équivalent) andpotassium carbonate (634 g, 4.6 mol, 2.0 équivalents). The vigorously stirredsuspension was heated to 125 °C for two hours or until the disappearance ofisovanillin. The reaction was cooled to 20 -30 °C and filtered to remove theinorganic salts. The filter cake was rinsed with methanol (1.0 L).

The clear, light-brown filtrate (DMF and methanol) containing the product, 3-cyclopentyloxy-4-methoxybenzaldehyde, was used directly in the next step (100% solution yield).

Example 2

Préparation of 3-Cyclopentyloxy-4-methoxybenzyl alcohol. A 12 liter round bottom flask equipped with an overhead stirrer, internaithermometer, and a reflux condensor equipped with a nitrogen inlet was flushed withnitrogen. The flask was charged with dimethylformamide (2.4 L), methanol (1.0 L),and 3-cyclopentyloxy-4-methoxybenzaldehyde (506 g, 2.3 mol, 1 équivalent). Thecontents of the flask were cooled to 0 to 5 °C followed by the addition of sodiumborohydride (32.2 g, 0.85 mol, 0.37 équivalents). The reaction was maintained at 0 \· 14 011144 to 5 °C for 30 minutes, and warmed to 20 to 25 °C for an additional 2 hours or untilthe disappearance of the aldéhyde. A solution of 6N hydrochloric acid (195 mL, 1.17 mol, 0.51 équivalents) was added over 20 minutes. The reaction wasconcentrated under reduced pressure, and cooled to 20 to 25 °C.

The flask was charged with deionized water (1.9 L) and toluene (1.9 L). Thelayers were separated, the organic layer was isolated, and washed twice withdeionized water (2 x 800 mL). The product, 3-cyclopentyloxy-4-methoxybenzylalcohol was collected as a solution in toluene (97% solution yield) and used directlyin the next step.

Example 3

Préparation of 4-Chloromethyl-2-cyclopentyloxy-l-methoxybenzene. A 12 liter round bottom flask equipped with an overhead stirrer, internaithermometer, and a reflux condensor equipped with a nitrogen inlet was flushed withnitrogen. The flask was charged with 3-cyclopentyloxy-4-methoxybenzyl alcohol(495 g, 2.2 mol, 1 équivalent) in a solution of toluene. To the vigorously stirredreaction at 22 °C was added concentrated hydrochloric acid (600 g, 2.75équivalents). The reaction was maintained at 20 to 25 °C for 30 minutes. The toporganic layer was isolated and the bottom acidic layer was discarded. To the toporganic layer was charged a solution of 10% sodium bicarbonate (550 g, 0.65 mol,0.36 équivalents) and t-butyl methyl ether (814 g). The contents of the flask werevigorously stirred, and allowed to settle. The product, 4-chloromethyl-2-cyclopentyloxy-l-methoxybenzene, was isolated as a solution in toluene and i-butyl methyl ether (96.8% solution yield). This was used directly in the next step.

Example 4

Préparation of 4-Cyanomethyl-2-cyclopentyloxv-l-methoxybenzene. A 12 liter round bottom flask equipped with an overhead stirrer, and adistillation apparatus was flushed with nitrogen. The flask was charged with 4-chloromethyl-2-cyclopentyloxy-1 -methoxybenzene (519 g, 2.15 mol, 1.0équivalents) in a solution of toluene and ί-butyl methyl ether. The reaction wasconcentrated under reduce pressure to a residue. To the 12 liter flask was chargedDMF (1.44 kg) and sodium cyanide (142 g, 2.9 mol, 1.35 équivalents). The reactionwas heated to 55 °C for 6 hours or until deemed complété by the disappearance ofthe benzyl chloride. The reaction was concentrated under reduced pressure to aresidue. To the flask was charged ί-butyl methyl ether (2.30 kg) and deionized water(800 mL). The contents of the flask were vigorously stirred, and allowed to settle.The top organic layer was isolated, washed three times with deionized water (3 x800 mL), and concentrated uiider atmospheric pressure to a residue. To the flaskwas added acetonitrile (1.26 kg) and the distillation was continued until an 15 011144 additional 400 mL of solvent was collected. The product, 4-cyanomethyl-2-cyclopentyloxy-l-methoxybenzene, was isolated as a solution in acetonitrile (92.2%yield). This was used directly in the next step.

Example 5

Préparation of Dimethyl-4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenvl)pimelate A 12 liter round bottom flask equipped with an overhead stirrer, internaithermometer, and a reflux condensor equipped with a nitrogen inlet was flushed withnitrogen. The flask was charged with a solution of 4-cyanomethyl-2- cyclopentyloxy-l-methoxybenzene (460 g, 1.99 mol, 1.0 équivalent) in acetonitrile,and methyl acrylate (520 g, 6.0 mol, 3.0 équivalents). The contents of the flask wascooled to -10 °C. A pressure equalizing addition funnel was charged withacetonitrile (1.1 L) and benzyltrimethyl ammonium hydroxide (a 40% w/w solutionin methanol, 25 g, 0.06 mol, 0.03 équivalents). The contents of the addition funnelwas added to the flask. An exotherm was observed, and after stirring for 30 minutesthe contents of the flask were cooled to 20 °C. The reaction was concentrated underreduced pressure to a residue. To the residue was added toluene (2.6 L). Thissolution of dimethyl-4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)pimelate ( 90% solution yield) was used directly in the next step.

Example 6

Préparation of 4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1-one A 12 liter round bottom flask equipped with an overhead stirrer, internaithermometer, and a reflux condensor equipped with a nitrogen inlet was flushed withnitrogen. The flask was charged with a solution of dimethyl-4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)pimelate ( 720 g, 1.78 mol, 1 équivalent) intoluene, and sodium methoxide (25 wt% in methanol, 545 g, 2.67 mol, 1.5équivalents). The reaction was heated to 70 to 75 °C for 2 hours or until deemedcomplété by the disappearance of the pimelate. The reaction was cooled to 25 °C. A solution of 6N hydrochloric acid was added in order to adjust the pH to 6.8 - 7.2,The reaction was concentrated under vacuum to a residue. The flask was chargedwith dimethylsulfoxide (3.3 L), deionized water (250 mL) and sodium chloride (250g)·

The contents of the flask were heated to 145-155 °C, and held at thistempérature for 2 hours. The reaction was cooled and concentrated under vacuumto a residue. To the residue was added water (1.9 L), ethyl acetate (1.25 L), and t-butyl methyl ether (620 mL). The solution was stirred and allowed to settle. Thelayers were separated, and the aqueous layer was re-extracted with ethyl acetate(1.25 L). The combined organic layers were washed twice with deionized water (2 16 011144 X 2.5 L). The organic layer was isolated and concentrated under reduced pressure toa residue. To this residue was added isopropanol (1.66 L) and heated to produce asolution followed by the slow addition of hexanes (1.66 L). The suspension wascooled to 5 °C over 30 minutes, and held at 0 to 5 °C for two hours. The productwas filtered and washed with 50-50 isopropanol-hexanes (840 mL) mixture at 0 °C.

The product was dried to afford 4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one (315 g, 56 % from the pimelate).

Example 7

Préparation of cis-(+/-)-6-i3-(cyclopentvloxy)-4-methoxyphenyn-1 - oxobicycloi2.51octane-2,6-dicarbonitrile. A 5 liter round bottom flask equipped with an overhead stirrer, internaithermometer, and a nitrogen inlet was flushed with nitrogen. The flask was chargedwith 50% potassium hydroxide (220 g) and tetrahydrofuran (550 mL). Whilestirring at room température, benzyltriéthylammonium chloride (8.1 g, 0.035 mol, 0.05 équivalent) was added. The solution was cooled to 0 °C. To a pressureequalizing addition funnel was charged a solution containing tetrahydrofuran (550mL), 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-l-one (230 g, 0.73 mol, 1.0 équivalent), and chloroacetonitrile (59 g, 0.78 mol, 1.07 équivalent) atroom température. While stirring the flasks contents at 0 °C, the solution in thepressure addition funnel was added over 15 minutes. The température wasmaintained between 0 and 5 °C, and stirred for one hour. The reaction was warmedto 25 °C, diluted with water (900 mL), and ethyl acetate (900 mL). The solution wasstirred and allowed to settle for 30 minutes. The layers were separated, the organiclayer was isolated, and concentrated by vacuum distillation to a residue. Methanol(540 mL) was added and the solution was heated to 40 °C. While cooling to 200 Cover 90 minutes, hexanes (540 mL) was added. Cooling was continued, and theproduct began to crystallize at 10 °C. The suspension was then cooled to -5 °C andheld at -5-0 °C for two hours. The product was filtered and washed with a 50-50methanol-hexanes mixture (300 mL) at 0 °C. The product was dried to afford cis-(+/-j-6-[3-(cyclopentyloxy)-4-methoxyphenyl]-1 -oxobicyclo[2.5]octane-2,6-dicarbonitrile (190 g, 73 %) as a white crystalline solid.

Example 8Préparation of l-9a

In a stoppered 12 dram screw-top vial was added diglyme (5.92 g) and the epoxy nitrile (0.70 g, leq) of Example 7. This mixture was stirred with heating in an oil bath for 5 min. Then MgB^'ôK^O (0.906 g, 1.55 eq) was added. After 3 hr no starting material was detected. The reaction mixture was cooled, then mixed with 5% aqueous citric acid/ethyl acetate and the layers shaken and separated. The 17 011144 second extraction with ether/ethyl acetate gave some color extracted into organiclayer; but the next extraction had no color. The organic fractions were combinedand washed with water and brine and dried with MgSOzj. The product wascrystallized from hexane; mp 151-152 °C.

Elemental analysis: C - 58.20, H - 5,82, Br -18.44, N - 6.46; found C -58.32, H - 5.73, Br -18.48 , N - 6.34. The structure was confirmed by X-raystructure détermination of a crystalline sample obtained from methyl alcohol.

Example 9Préparation of l-9b

To Mg (0.189 g, 2.02 eq) (polished with mortar and pestle) in ether wasadded 1,2-dibromoethane (1.55 g, 2.06 eq) in a small volume of ether to initiate theGrignard. When most of the magnésium was consumed and no more évolution ofethane was observed, the reaction was stirred for an additional 0.5 hr at roomtempérature after which was added the epoxide of Example 7 (1.41g; 1 eq) in aminimal amount of dry tetrahydrofuran at ambient température. After about 70 hr atroom température there was obtained both the bromo cyanoalcohol (l-9b) andbromo cyanohydrin (l-9a) in a ratio of 6:1. The l-9b product was isolated as an oilby prepartive HPLC. The structure was confirmed by carbon and proton NMR.

Example 10

Préparation of Compound 3-1 - Epoxvsulfone

To a 25ml round-bottom flask equipped with a magnetic stir bar and a rubberseptum was charged 1.00 g of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one, 0.70 g of chloromethyl p-tolylsulfome, and 7 mlof tetrahydrofuran. This was stirred, then 3 ml of 50% w/w aqueous NaOH andbenzyltrimeth ch (0.05g) was added. This suspension was vigorously stirred for 2hours at room température. The reaction solution was transferred to a separatoryfunnel to which was added 50 ml of ethyl acetate and acidified with 6N HCl. Theorganic layer was retained, washed 2X with deionized water, dried with MgSCty andfilterêd to remove the salts.

Example 11

Préparation of Compound 3-2 - Bromoaldehvde

To magnésium (0.048g, 1.03 eq, 0.021 mol; polished with mortar and pestle)in ether was added 1,2-dibromoethane (0.40 g, 1.06 eq, 0.02 mol) under nitrogen.Two drops of iodine were added in ether to start the reaction, after which thereaction was heated gently. Once the Grignard had formed, the reaction flask wascooled to about 5 °C and the epoxysulfone of Example 10 (0.93 g, 1 eq, 0.002 mol)was added in ether/methylene chloride. The reaction was followed via TLC(conditions: silica gel with cyclohexane:toluene:acetonitrile:acetic acid 40:40:20:4). 18 011144

The reaction was stirred at 5° for 2 hours. The product was isolated by adding waterand ether/TBME to the reaction mixture, and seperating the organic layers. Thesewere washed with water and brine and dried over MgSOzp Evaporation gave an oilwhieh was flash chromatographed over 40 g of silica gel using a mixture of hexaneand ethyl acetate (5-40% ethyl acetate). This gave a clear oil (0.49 g) containingabout equal proportions of the equitorial and axial isomers as determined by protonNMR. Mass specrum showed a molecular ion at m/e 405 containing 1 bromineatom [C2oH24BrN03].

Example 12

Préparation of c-4-cyano-4-(3-cyclopentyIoxy-4-methoxyphenyl)-r- cvclohexanecarboxylic acid. A 5 liter round bottom flask equipped with an overhead stirrer, internaithermometer, and a reflux condensor equipped with a nitrogen inlet was flushed withnitrogen. The flask was charged with dimethylformamide (580 g), acetonitrile (480g), lithium bromide (72 g, 0.83 mol, 1.62 équivalents) and deionized water (20 g, 1.1mol, 2.2 équivalents). The solution was stirred under nitrogen at 25 - 30 °Cfollowed by the addition of cis-(+/-)-6-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-oxobicyclo[2.5]octane-2,6-dicarbonitrile (180 g, 0.51 mol, 1.0 équivalent). Thereactor was heated to 90 - 95 °C for 8 hours or until deemed complété by thedisappearance of epoxy nitrile. The contents of the flask was cooled to 20 °C,followed by the addition of a sodium hydroxide solution (92 g of sodium hydroxide,2.3 mol, 4.5 équivalents, dissolved in 200 mL of deionized water). The suspensionwas stirred at 20 °C for 30 minutes followed by the addition of sodium hypochlorite(600 mL, 0.46 mol, 0.9 équivalents). The contents of the flask were stirred for 90minutes followed by the addition of t-butyl methyl ether ( 2.27 kg) and 6N HCl (644mL, 3.86 mol, 7.5 équivalents). The bottom aqueous layer was back-extracted withί-butyl methyl ether (454 g), and the combined organic layer was washed four timeswith deionized water (4 X 800 mL). The organic layer was concentrated to aresidue. To the flask was charged ethyl acetate (900 g) and heated to reflux. Thecontents of the flask was cooled to 50 °C followed by the addition of hexanes (672g). The contents of the flask were cooled to 0 °C and held for 1 hour. The productwas filtered and washed with cold ethyl acetate / hexanes (1/9,175 g). The productwas dried to afford c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-cyclohexanecarboxylic acid (125 g, 69 %) as an off-white powder.

Example 13

Préparation of c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r- cyclohexanecarboxvlic acid chloride 19 011144

In a 1 neck flask equipped for nitrogen flow was combined c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-cyclohexanecarboxylic acid (1.372g, 1 eq, 0.004 mol) and oxalyl chloride (4.568g, 9eq, 0.036 mol). One drop of dimethylformamide was then added. This mixture was stirred at ambient températureovemight. After évaporation under high vacuum this yielded the captioned product.

Example 14

Préparation of Form l-10a - 4-cyano-4-(3-cyclopentvloxv-4- methoxyphenvl)-r-cyclohexane acvl nitrile

In a flask a sample of the acid chloride (0.217 g, 0.006 mol, 1 eq) prepared inExample 12 was dissolved in CDCI3 (2.34 mL). To this was solution (cooled to5°C) was added trimethylsilyl cyanide (0.07g, 1.3 eq, 0.008 mol.) and a catalyticamount of ZnÏ2 (0.004g). This solution was refluxed ovemight. This yielded0.21 lg of the captioned product. IR: COCN, v 2220 cm'l; C=O, V 1720cm"k Theisomeric purity of l-10a was determined by hydrolyzing the acyl nitrile in warmwater, the product being essentially pure compound 1-1 la.

Example 15

Préparation of Form l-10b of 4-cyano-4-(3-cyclopentyloxv-4- methoxvphenyl)-r-cyclohexane acyl nitrile

In an experiment analogous to Example 14, the axial carboxylic acid wasconverted to the acid chloride using oxalyl chloride and catalytic amount of dimethylformamide. This acid chloride was converted directly to the corresponding acylnitrile, 1- 10b, the isomer of the compound prepared in Example 14. The isomericpurity was assayed by hydrolyzing the acyl nitrile by stirring it in warm water for 20hours. Analytical HPLC détermination showed that > 96% of the product had theformof l-10b.

Claims (5)

1. 20 011144 What is claimed is:

   1. A method for making a compound of formula I RiX

   R' (I) R! is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties may beoptionally substituted with one or more halogens; m is 0 to 2;n is 1 to 4;r is 0 to 6; R4 and R5 are independently selected from hydrogen or a Ci-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7.11 polycycloalkyl,tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl,tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containingone or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties maybe optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when Rg is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in -(CR4R5)nO(CR4R5)niR6> X is YR2, halogen, nitro, NH2, or formyl amine; X2 is O or NR8; Y is O or S(O)m’;m’isO, l,or2; R2 is independently selected from -CH3 or -CH2CH3 optionally substitutedby 1 or more halogens; R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, -CH=CR8’R8\ cyclopropyl optionally substituted by R8\ 21 011144 CN, OR8, CH2OR8, NRsRlO» CH2NR8R10. C(Zr)H, C(O)ORs, C(0)NRsRlO, or CsCR8’ Rg is hydrogen or (4.4 alkyl optionally substituted by one to three fluorines;Rg’ is R8 or fluorine; RjOis OR8orRn; R j 1 is hydrogen, or C44 alkyl optionally substituted by one to threefluorines; Z’ is O, NR9, NOR8, NCN, C(-CN)2, CRgCN, CR8NO2, CRgC(O)OR8,CR8C(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NR8R8; R’ and R" are independently hydrogen or -C(O)OH;which method comprises treating a compound of formula Π

   where Rp R3, X2 and X are the same as for formula (I), with lithiumbromide in a polar solvent at a température between about 60° and 100° C,optionally under an inert atmosphère for a time sufficient for the reaction to go tocompletion.
2. 2. The method of claim 1 wherein R1X2 is cyclopentyloxy and X ismethoxy
3. 3. A compound of formula Π

   R! is-(CR4R5)nC(O)O(CR4R5)mR6,-(CR4R5)nC(O)NR4(CR4R5)mR6,-(CR4R5)nO(CR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties may beoptionally substituted with one or more halogens; ' m is 0 to 2;n is 1 to 4;r is 0 to 6; R4 and R5 are independently selected from hydrogen or a Ci-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCl-3alkyl, halo substituted aryloxyCl-3 alkyl, indanyl, indenyl, C7-H polycycloalkyl,tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, 22 C11144 tetrahydrothiopyranyl, thiopyranyl, C3_6 cycloalkyl, or a C4.6 cycloalkyl containingone or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties maybe optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when R.6 is hydroxyl, then m is 2; or b) when Rô is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then Rô is other than H in-(CR4R5)nO(CR4R5)mR6; X is YR2, halogen, nitro, NH2, or formyl amine; X2 is O or NR8; Y is O or S(O)nT,m’is 0, l,or2; R2 is independently selected from -CH3 or -CH2CH3 optionally substitutedby 1 or more halogens; R3 is hydrogen, halogen, Ci-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, -CH=CR8’R8’» cyclopropyl optionally substituted by R8\ CN, ORg, CH2OR8, NRsRlO, CIùNRgRlO, C(Z0H, C(O)ORg, C(O)NRsRl0, orC=CR8’ Rg is hydrogen or Ci,4 alkyl optionally substituted by one to three fluorines; Rg> is R8 or fluorine; RiOisORsorRii; Rl 1 is hydrogen, or Ci_4 alkyl optionally substituted by one to threefluorines; Z’ is O, NR9, N0R8, NCN, C(-CN)2, CRgCN, CRgNO2, CR8C(O)ORg,CRgC(O)NR8R8, C(-CN)NC>2, C(-CN)C(O)OR9, or C(-CN)C(O)NRgRs, and . T is CN or SO2R where R is Cj^alkyl or C()_3alkylphenyl.
4. 4. The compound of claim 3 wherein in the resulting compound R1X2is cyclopentyloxy and X is methoxy.
5. 5. An invention as describéd herein comprising either a process formaking a compound of formula I as described in claim 1 or any intermediated orintermediate step in that process.